RESUMEN
Yellow fever virus (YFV) is a human Flavivirus reemerging in parts of the world. While a vaccine is available, large outbreaks have recently occurred in Brazil and certain African countries. Development of an effective antiviral against YFV is crucial, as there is no available effective drug against YFV. We have identified several novel nucleoside analogs with potent antiviral activity against YFV with 50% effective concentration (EC50) values between 0.25 and 1 µM with selectivity indices over 100 in culture.
Asunto(s)
Antivirales/uso terapéutico , Nucleósidos/análogos & derivados , Nucleósidos/uso terapéutico , Fiebre Amarilla/tratamiento farmacológico , Virus de la Fiebre Amarilla/efectos de los fármacos , Virus de la Fiebre Amarilla/patogenicidad , África , Animales , Brasil , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Estructura Molecular , Células Vero , Fiebre Amarilla/virologíaRESUMEN
Exploration of the chemical space of known influenza polymerase PB2 inhibitor Pimodivir, was performed by our group. We synthesized and identified compounds 16a and 16b, two novel thienopyrimidine derivatives displaying anti-influenza A activity in the single digit nanomolar range in cell culture. Binding of these unique compounds in the influenza polymerase PB2 pocket was also determined using molecular modeling.
Asunto(s)
Antivirales/química , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Piridinas/química , Pirimidinas/química , Pirroles/química , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas Virales/metabolismo , Células A549 , Secuencia de Aminoácidos , Animales , Antivirales/farmacología , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Piridinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Over the past decades, both 4'-modified nucleoside and carbocyclic nucleoside analogs have been under the spotlight as several compounds from either family showed anti-HIV, HCV, RSV or SARS-CoV-2 activity. Herein, we designed compounds combining these two features and report the synthesis of a series of novel 4'-substituted carbocyclic uracil derivatives along with their corresponding monophosphate prodrugs. These compounds were successfully prepared in 19 to 22 steps from the commercially available (-)-Vince lactam and were evaluated against a panel of RNA viruses including SARS-CoV-2, influenza A/B viruses and norovirus.
Asunto(s)
COVID-19 , Virus de la Influenza A , Profármacos , Humanos , Antivirales/farmacología , Anticuerpos contra la Hepatitis C , Virus de la Influenza B , Nucleósidos , Profármacos/farmacología , SARS-CoV-2 , UraciloRESUMEN
Based on the anti-hepatitis C activity of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine, a series of new modified purine 2'-C-methyl nucleosides was prepared as potential anti-hepatitis C virus agents. Herein, we report the synthesis of both 6-modified and 2-modified purine 2'-C-methyl-nucleosides along with their anti-HCV replication activity and cytotoxicity in different cells.